Understanding the Pathophysiology of Type 2 Diabetes in Navajo Youth

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PROJECT ABSTRACT Type 2 diabetes (T2D) is on the rise among youth in the US and worldwide, and disproportionately affects racial and ethnic minority populations including American Indians. The number of at-risk youth continues to increase alongside the child obesity epidemic, with an unprecedented proportion of youth developing T2D during puberty. The public health implications of this trend are highly significant, as debilitating complications are likely to manifest by early adulthood during what should be the most active and productive years of life. Prevention of youth-onset T2D is crucial as the course of disease is more aggressive than the typical “adult-onset T2D”. Yet current knowledge of the pathophysiology of youth-onset T2D is limited, so it is still unclear whom to target or how to prevent youth-onset T2D. Puberty is a critical period for T2D development, as this life stage is characterized by marked changes in insulin sensitivity that do not always resolve by the end of puberty. Prior studies largely used cross-sectional or case-control designs, or longitudinal protocols that rarely spanned the duration of puberty, precluding a holistic synthesis of how longitudinal patterns of change in biomarkers of glucose-insulin homeostasis culminate in youth-onset T2D. Deciphering the pathways leading to youth-onset T2D is fundamental to understanding pre-clinical disease progression, which has potential to directly inform targeted prevention approaches. With RFA-DK-21-002, the NIDDK seeks to establish a cohort of early pubertal youth at risk for T2D to better understand the pathophysiology of youth-onset T2D. We propose here a Colorado|Navajo clinical site that will recruit for this consortium 400 rural-dwelling American Indian youth, the subgroup at highest risk for youth-onset T2D. Under leadership from the University of Colorado, this clinical site will be based in a rural community on the Navajo Nation where we have conducted youth diabetes research since 2000. We will enroll youth in early puberty (Tanner Stages 2-3) who have elevated risk for youth-onset T2D based on overweight or obesity status (BMI ≥85th percentile) and self-identification with American Indian race. Participants will be followed for 33 months, on average, undergoing annual 2-hour oral glucose tolerance tests (n= 3-4 per participant) and semi-annual visits (n= 3-4 per participant) for collection of additional biospecimens and data on physiological, behavioral, familial, and psychosocial factors associated with T2D risk. Our specific aims are: 1) locally, recruit 400 American Indian youth in the early stages of puberty (Tanner stage 2-3) with overweight or obesity, and follow them longitudinally to assess the risk of T2D; 2) across the consortium, identify patterns of change in biomarkers of glucose-insulin homeostasis that culminate in development of youth- onset T2D; and 3) across the consortium, develop prediction models for youth-onset T2D and identify sub- phenotypes of incident youth-onset T2D.